Long-term Survival Happens With Targeted Rx in Melanoma

Pam Harrison

October 18, 2017

Contrary to prevailing belief, targeted therapy for patients with metastatic melanoma can result in long-term survival, suggests a 5-year landmark analysis, which has the longest-follow-up any randomized trial of its kind.

The targeted therapy was the combination of dabrafenib (Tafinlar, Novartis), a BRAF inhibitor, and trametinib (Mekinist, Novartis), an MEK inhibitor. The study patients all had BRAF V600-mutant melanomas.

"It is clear a significant proportion of better-prognosis patients at the start of therapy do very well for several years and counting," Keith Flaherty, MD, director, Henri and Belinda Termeer Center for Targeted Therapies, Massachusetts General Hospital Cancer Center, Boston, told Medscape Medical News in an email.

"Having treated some of these patients for as long as 6 to 7 years, I can speak to the fact that once patients have survived 3 years or so on this [combination] therapy, the likelihood that they will continue to do well is quite high," he added.

"So these findings defy predictions that were made in the early years of BRAF inhibitor–based therapy trials, and even today, you will see fictionalized outcome data that show no long-term survivors on [this] therapy," Dr Flaherty said.

These findings defy predictions that were made in the early years. Dr Keith Flaherty

The new study was published online October 9 in the Journal of Clinical Oncology.

Dr Flaherty was referring to the fact that many ― but not all ― patients with advanced melanoma who received targeted therapy in early trials responded but then developed resistance to treatment.

In the current study, all of the patients enrolled in an open-label, phase 1 and 2 study had unresectable stage IIIC or IV BRAF V600E/K-mutant melanoma. Only those who participated in part C of the open-label trial were included in this 5-year landmark analysis.

On initial enrollment, all patients were naive to both dabrafenib (D) and trametinib (T). They were randomly allocated to receive D monotherapy, at a dose of 150 mg given twice a day, or to D at a dose of 150 mg given twice a day along with T 1 mg given once a day (D + T 150/1) or to the same dose of D plus T at a dose of 2 mg/day (D + T 150/2).

It is noteworthy that the study was not powered to compare outcomes between those assigned to the D + T 150/1 and those who received the D + T 150/2, and results were not reported for the D + T 150/1 group.

"One hundred sixty-two patients were enrolled in part C, with three groups of 54 patients each randomly assigned to receive D monotherapy, D + T 150/1, or D + T 150/2," the authors explain.

At data cutoff in October 2016, the minimum follow-up for the study cohort overall was 60 months from the time of randomization, they add.

At a median follow-up of 66.5 months, 91% of patients in the D-alone arm and 80% of those in the D + T 150/2 arm had experienced disease progression or had died.

This translated into a progression-free survival (PFS) rate at 4 and 5 years of 13% for those in the D + T 150/2 treatment arm and only 3% for the monotherapy arm.

At 4 years, 30% of patients in the combination arm were still alive; a similar percentage, 28%, were alive at 5 years, the investigators report.

For those in the D monotherapy arm, 23% and 21% were still alive at 4 and 5 years, respectively.

As was permitted by the study protocol, the majority of the initial 54 patients randomly assigned to D monotherapy, at 83%, crossed over to the D + T 150/2 arm on disease progression, and almost all of these patients received additional anticancer therapy.

However, PFS rates were substantially influenced by the initial response to treatment.

For example, the PFS rate was 67% at 3 years and 40% at both 4 and 5 years among patients who achieved a complete response (CR) to the initial D + T 150/2 regimen.

For those who achieved a partial response (PR) to the same combination regimen, PFS rates were 13%, 9%, and 9% at years 3, 4, and 5, respectively, after treatment initiation. The median PFS for this subgroup of patients was 10 months.

Similarly, overall survival (OS) rates were greatly modified by patients' initial response to the D + T 150/2 regimen. Two thirds of patients who experienced CR were alive at 3 years, 56% at 4 years, and 44% at 5 years.

OS rates for patients who achieved a PR to the same combination strategy were 31% at 3 years, 22% at 4 years, and 22% at 5 years. The median OS for this subgroup of patients was 22.9 months, the investigators report.

"The median duration of response was 10.5 months...in the D + T 150/2 arm and 5.6 months...in the D monotherapy arm," study authors add.

Favorable Prognostic Factors Associated With Longer Benefit

Perhaps not surprisingly, favorable prognostic factors also influenced PFS and OS rates.

For example, 23% of patients with normal baseline serum lactate dehydrogenase (LDH) levels who received the D + T 150/2 regimen were alive and free of disease progression at 4 and 5 years, as were 6% in the D monotherapy arm.

At 4 years, 48% of those in the D + T 150/2 arm were still alive, as were 45% at year 5.

By comparison, the OS rate was 31% of patients in the D monotherapy arm at 4 years and 26% at 5 years.

In contrast, none of the patients whose baseline LDH level was greater than the upper limit of normal were free of disease progression at 5 years, and OS rates in both the D + T 150/2 group and the monotherapy group were low.

The median duration of treatment was 10.9 months for the D + T 150/2 arm and 6.1 months for the monotherapy arm.

Commenting on these findings, Dr Flaherty said that the most "striking" observation is that patients who remained progression free beyond 2 years were those whose disease had lower-risk features at baseline.

"This is not to say that patients with higher-risk features can't benefit from treatment," Dr Flaherty added, "but they do so for a limited period of time ― so if one only offers this therapy to patients with high-risk features, I've never witnessed long-term disease control and survival," he said.

Not unexpectedly, serious adverse events (AEs) were more likely to occur with the combination regimen than with D monotherapy.

As was previously reported, pyrexia was the most commonly reported AE, but incidence rates of pyrexia remained stable at 5 years' follow-up, and only 16% of patients who received D + T 150/2 discontinued treatment after 5 years because of an AE, the investigators add.

When pyrexia does occur, physicians simply need to stop treatment for a few days, introduce an antipyretic, such as acetaminophen, and restart the regimen a few days later.

"Fever generally resolves within a day when treatment is withheld," Dr Flaherty observed. "So we are very quick to use treatment interruption as the first approach to treat fever," he added.

Oncology Urban Legend

Asked by Medscape Medical News to comment on the study, Michael Wong, MD, PhD, professor of medicine, MD Anderson Cancer Center in Houston, Texas, cautioned that this was a small study to start with and by the time patients had experienced disease progression or had died, the number of participants was very small.

Nevertheless, he agreed with Dr Flaherty that it is an "oncology urban legend" that patients with metastatic melanoma will initally experience rapid response to targeted treatment, but their condition will then rapidly deteriorate because of resistance.

"All of us who treat melanoma ― and just melanoma ― for a living have seen it where patients come in and you put them on D and T and then every clinic visit is a white knuckle event because you are asking: 'Is this the time [resistance] is going to happen?' " he observed.

"What this study tells us is that a proportion of patients are going to be all right," Dr Wong added.

Dr Wong also pointed out that the patients who do well on targeted therapies also do well on immunotherapy: "So the big question is, What do we do with poor-prognostic-feature patients?" he asked.

In the current study, almost all patients who were treated with D monotherapy (93%) received subsequent anticancer therapy, as did 54% of those in the combination group, with a good third of them receiving immunotherapy.

"Not everybody gets a response to targeted therapies, and progression very often happens," Dr Wong said.

"So when progression happens, you put patients on downstream therapy, and I believe that this downstream therapy does make a difference ― otherwise, patients would not be alive," he added.

"My take-away from this study is that D and T does not prejudice you against using further medicines that can make a difference to survival," Dr Wong concluded.

The study was supported by GlaxoSmithKline. Dabrafenib and trametinib have been Novartis assets since March 2, 2015. Dr Flaherty has served as a consult or an advisor to Novartis and has received research funding from Novartis. Other authors have disclosed relationships with industry, as listed in the published article. Dr Wong has disclosed no relevant financial relationships.

J Clin Oncol. Published online October 9, 2017. Abstract

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